Opioid compounds remain key agents for the treatment of a wide variety of acute and chronic pain. The World Health Organization has recommended morphine as the analgesic of choice for the treatment of severe cancer pain. Additionally, morphine and related opioids are widely used to alleviate moderate to severe pain after surgery or trauma, or associated with medical illness including, but not limited to, solid or blood borne tumors. Patients with apparently similar pain states have large differences in opioid dosing requirements. Factors that contribute to this variability include type of pain (nociceptive, inflammatory, neuropathic or mixed) and its severity, concurrent medications, gender and other genetic aspects, and whether patients are opioid-naive or tolerant.
Unfortunately, the effects produced by morphine and similar opioid compounds make them amenable to abuse and are associated with many undesirable side effects, all mediated through activation of the mu (MOR) and other opioid receptors. They include physical and psychological dependence leading to addiction and other diverse pathophysiological states. Other undesirable side effects associated with the use of opioids include nausea and vomiting, drowsiness, respiratory depression and gastrointestinal and bladder dysfunction.
In addition to the adverse physiological effects listed above, a major associated risk is that repeated daily administrations of morphine or morphine-like opioids will eventually induce significant tolerance to the therapeutic effects of the drug, as well as initiating some degree of physical dependence. Opioid tolerance is a phenomenon whereby chronic exposure to a drug diminishes its anti nociceptive or analgesic effect, or creates the need for a higher dose to maintain its effect.
One undesirable effect of opioid tolerance is that the higher opioid requirements of highly tolerant patients treated for pain increase the likelihood of unpleasant non-analgesic side effects due to greater circulating concentrations of opioids and potentially toxic opioid metabolites (M. T. Smith, Clin. Exp. Pharmacol. Physiol. 27, 524-528 (2000); F. B. Ross & M. T. Smith, Pain, 73, 151-157 (1997)).
There is a need for improved methods and compositions for the effective alleviation of pain in patients while minimizing or avoiding the undesired side effects associated with opioid receptor agonists.
The opioid receptor is thought to have four receptor subtypes named mu (morphine receptor), sigma (the phencyclidine receptor), kappa (the ketocyclazocine receptor) and delta (the endorphinlenkephalin receptor). The biochemical and cellular effects of morphine, including analgesia, are transduced through the mu opioid receptor (MOR), found in high concentrations within the central nervous system (CNS). The World Health Organization's guidelines for the management of chronic cancer pain recommend that clinicians reserve strong opioids such as oxycodone and morphine for the relief of moderate to severe cancer pain (World Health Organization, 1986) and that two strong opioids should not be co-administered, presumably because it is generally thought that all opioids exert their analgesic effects through the same receptor mechanisms in the CNS.
However, recent studies by Maree Smith and co-workers have shown that the antinociceptive effects of structurally related oxycodone and morphine are differentially antagonized by nor-BNI (a κ-selective opioid antagonist) and naloxonazine (selective μ-opioid receptor antagonist), indicating that they produce antinociception through different opioid receptor mechanisms (see F. B. Ross & M. T. Smith, Pain, 73: 151-157 (1997)). Furthermore, it has been found that co-administration of sub-anti nociceptive doses of oxycodone with morphine to rats results in synergistic levels of antinociception (F. B. Ross et al., Pain, 84, 421-428 (2000)). Importantly, it was found that animals that received the sub-antinociceptive doses of oxycodone and morphine were similar to control animals with respect to CNS side effects. Administration of equipotent-doses of either opioid alone resulted in sedation of the rats. This may suggest that co-administration of sub-analgesic or analgesic doses of oxycodone and morphine to patients may provide synergistic antinociceptive relief with a reduction of CNS-related side effects.
It is known that opioid agonists and antagonists bind in different manners to their respective binding sites and potentially influence the agonist or antagonist response of other molecules, when administered in combination. For example, Holaday et al. reported the cross reactivities of kappa and mu agonists and antagonists in a rat endotoxic shock and rat fluorothyl seizure models and the effects on in vivo changes in striatal cyclic adenosine monophosphate (cAMP) (J. Holaday et al., Research Monograph 71, National Institute on Drug Abuse, 173-187). The authors reported that certain mu antagonists prevent the delta antagonists from blocking or reversing delta agonist effects. For example, it was reported that administration of the mu antagonists naloxazone or β-funaltrexamine (β-FNA) prior to the δ-selective antagonist ICI 154,129 or high doses of naloxone in rats subjected to endotoxemia, resulted in the δ-antagonists no longer effectively reversing endotoxic shock hypotension.
Dosaka-Akita et al. reported that administration of the selective kappa opioid agonist U-50,488H, which by itself had no significant effect on respiration or cardiovascular function, antagonized the acidotic, hypoxemic and hypercapnic effects of subsequently administered mu receptor agonist [D-Ala2,N-Methyl-Phe4, Gly-ol]enkephalin (DAMGO). Administration of U-50,488H prior to administration of DAM GO substantially eliminated the effect of DAMGO on arterial pH, PaO2 and PaCO2. Pretreatment with U-50,488H significantly antagonized morphine-induced acidosis, hypercapnemia and hypoxemia. However, pre-treatment with U-50,488H did not antagonize the morphine effect on increased respiratory rate. This observation highlights the complex nature of opioid agonist and antagonist interaction and the unpredictability of the effect of sequentially administering multiple opioid receptor agonists and/or antagonists.
The present invention provides methods and compositions for the alleviation of pain in a patient comprising the sequential administration of mu and/or kappa opioid receptor agonists to the patient. The methods and compositions provided herein are effective for the alleviation of pain while decreasing certain undesirable side effects of opioid analgesics.